Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[N:24]1[C:32]2[C:27](=[C:28]([N:33]3[CH:37]=[C:36]([C:38]4[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=4)[N:35]=[CH:34]3)[CH:29]=[CH:30][CH:31]=2)[C:26]([CH:44]([CH3:46])[CH3:45])=[N:25]1)[C:19]#[N:20].FC(F)(F)C(O)=O.[CH3:54][C:55]([CH3:57])=O>ClCCl>[CH:44]([C:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][C:28]=2[N:33]2[CH:37]=[C:36]([C:38]3[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=3)[N:35]=[CH:34]2)[N:24]([C:23]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=2[NH:15][CH:55]([CH3:57])[CH3:54])[N:25]=1)([CH3:46])[CH3:45]
Reactant: CC(C)=O
Reactant: CC(C)c1nn(-c2ccc(C#N)cc2N)c2cccc(-n3cnc(-c4cccnc4)c3)c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Nc1cc(C#N)ccc1-n1nc(C(C)C)c2c(-n3cnc(-c4cccnc4)c3)cccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium triacetoxyborohydride (192 mg) was added to a solution of compound (10b) (190 mg) in dichloromethane (2.7 mL), and the mixture was cooled to 0° C. Then trifluoroacetic acid (0.45 mL) and acetone (67 μL) were added thereto and the mixture was stirred at the same temperature for 30 minutes. After completion of the reaction, the reaction solution was partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The organic layer was washed with saturated brine and dried by the addition of anhydrous sodium sulfate. After removal of the solvent by evaporation, the residue was purified by neutral silica gel column chromatography (chloroform/methanol) to obtain compound (10c) (208.6 mg, yield 990) as a white foamy substance.
Reaction SMILES: [CH2:1]([N:15]1[C:24](=[O:25])[C:23]2[N:22]([CH3:26])[CH:21]=[N:20][C:19]=2[N:18]([CH3:27])[C:16]1=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=[CH2:14].C[N+]1([O-])CC[O:32]CC1.[OH2:36].S([O-])([O-])=O.[Na+].[Na+]>CC(C)=O.O>[OH:36][CH:13]([CH2:14][OH:32])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][N:15]1[C:24](=[O:25])[C:23]2[N:22]([CH3:26])[CH:21]=[N:20][C:19]=2[N:18]([CH3:27])[C:16]1=[O:17]
Reactant: C=CCCCCCCCCCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Reactant: C[N+]1([O-])CCOCC1
Reactant: O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Cn1cnc2c1c(=O)n(CCCCCCCCCCCCC(O)CO)c(=O)n2C
Reaction time: 1 h
Yield: 96 %

Procedure:
A solution of 1-(13-Tetradecenyl)-3,7-dimethylxanthine (2.00 g, 5.35 mmol), 4-methylmorpholine-N-oxide (2.72 mL, 60% wt in water, 15.8 mmol) and potassium osmate dihydrate (21 mg, 0.05 mmol) in acetone/water 3:1 (80 mL) was stirred for 16 hours. Water (100 mL) and sodium sulfite (1 g) were added and stirred for 1 hour. The reaction mixture was extracted with dichloromethane (3×100 mL) and the organic phase dried (magnesium sulfate) and evaporated to yield 2.10 g (96% yield) 1-(13,14-Dihydroxytetradecyl)-3,7-dimethylxanthine as a white solid.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[CH:10][C:11]2[CH2:12][C@H:13]3[N:24](C)[CH2:23][CH2:22][C@@:19]4([C:20]=2[CH:21]=1)[C@H:14]3[CH2:15][CH2:16][CH2:17][CH2:18]4)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:39]([O:41][CH2:42][C:43]([Cl:46])([Cl:45])[Cl:44])=[O:40]>CCOCC>[O:1]([C:8]1[CH:9]=[CH:10][C:11]2[CH2:12][C@H:13]3[N:24]([C:39]([O:41][CH2:42][C:43]([Cl:46])([Cl:45])[Cl:44])=[O:40])[CH2:23][CH2:22][C@@:19]4([C:20]=2[CH:21]=1)[C@H:14]3[CH2:15][CH2:16][CH2:17][CH2:18]4)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CN1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(Oc2ccccc2)cc13
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: c1ccccc1
Product: O=C(OCC(Cl)(Cl)Cl)N1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(Oc2ccccc2)cc13
Yield: 98.2 %

Procedure:
To a mixture of 2.3 g (0.007 mol) of (-)-3-phenoxy-N-methylmorphinan, 150 ml of benzene and 0.35 g of potassium carbonate was added dropwise, 3.3 g of 2,2,2-trichloroethyl chloroformate. The reaction mixture was stirred at reflux for 6 days. The mixture was diluted with ether and extracted with 4 N hydrochloric acid. The organic phase was washed with dilute ammonium hydroxide, water, and dried. Removal of solvent gave 3.4 g (99%) of the product (-)-3-phenoxy-N-trichlorocarbethoxymorphinan. For analysis, a sample of this compound was distilled, bp 230°-240°/0.05mmHg, [α]25D -119.65° (c 0.95, MeOH).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:24]([NH2:26])=O)=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[C:20]([Cl:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=3[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]21.C(N(CC)CC)C.S(Cl)(Cl)=O>CN(C)C=O.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:24]#[N:26])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[C:20]([Cl:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=3[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]21
Reactant: NC(=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(Cl)cc(Cl)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(Cl)c2nc3n(c12)CCCN3c1c(Cl)cc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 77.3 %

Procedure:
To a mixture of 9-chloro-1-(2,4,6-trichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carboxamide (430 mg, 1.00 mmol) and triethylamine (1.39 mL, 9.97 mmol) in N,N-dimethylformamide (5 mL) was added thionyl chloride (0.216 mL, 3.00 mmol) at 0° C., and the mixture was stirred at 0° C. for 10 min. After the mixture was diluted with aqueous sodium bicarbonate, the resultant mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 20-50% ethyl acetate/n-hexane gradient mixture to give the title compound as a yellow solid (317 mg, 0.773 mmol, 77%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.I[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21].Cl.CN(C)CC(O)=O>O1CCOCC1.[Cu]I>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][C:18]([O:12][C:9]2[CH:10]=[CH:11][C:6]([C:2]3[S:1][CH:5]=[CH:4][N:3]=3)=[CH:7][CH:8]=2)=[CH:19][CH:14]=1
Reactant: COc1ccccc1I
Reactant: Oc1ccc(-c2nccs2)cc1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(Oc2ccc(-c3nccs3)cc2)cc1
Temperature: 100 °C
Yield: 85.4 %

Procedure:
A mixture of product from step 3 (0.55 g, 3.1 mmol), iodoanisole (1.1 g, 4.6 mmol), CsCO3 (3.0 g, 9.2 mmol), N,N-dimethylglycine HCl (0.43 g, 3.1 mmol) and CuI (0.3 g, 1.5 mmol) in dioxane (40 mL) was heated to 100° C. for 3 days. After the solids were filtered off, the filtrate was partitioned with EtOAc/H2O, washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by a column chromatography on silica gel to yield the title compound (0.75 g, 90%). 1HNMR (400 MHz, CDCl3) δ 3.82 (s, 3H), 6.90 (d, J=8 Hz, 2H), 6.97 (d, J=8.8 Hz, 2H), 7.03 (d, J=8.8 Hz, 2H), 7.28 (d, J=3.6 Hz, 1H), 7.81 (d, J=3.6 Hz, 1H), 7.90 (d, J=8.8 Hz, 2H), MS m/z 284 (M+1).
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH:16]([CH3:20])[C:17]([OH:19])=[O:18].Cl.[CH2:22](O)[CH3:23]>>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH:16]([CH3:20])[C:17]([O:19][CH2:22][CH3:23])=[O:18]
Reactant: CC(C(=O)O)c1ccc2c(c1)CCc1ccccc1S2
Reactant: CCO
Agent: Cl
Product: CCOC(=O)C(C)c1ccc2c(c1)CCc1ccccc1S2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 100 mg of 2-(10,11-dihydro dibenzo[b,f]thiepin-2-yl)-propionic acid was added 2 ml of ethanol containing 17% of hydrogen chloride and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off to obtain the residue, to which was added ice-water and extracted with ethyl acetate, and the extract was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain pale brown oil, which was chromatographed over silica gel and eluted with benzene-chloroform. There was obtained 96 mg of ethyl 2-(10,11-dihydro dibenzo[b,f]thiepin-2-yl)-propionate as pale yellow oil.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:7]=[N:8][N:9]([CH3:11])[CH:10]=1)=[O:5].[CH2:13]([Mg]Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1>[CH3:11][N:9]1[CH:10]=[C:6]([C:4](=[O:5])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=[N:8]1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: CON(C)C(=O)c1cnn(C)c1
Solvent: C1CCOC1
Product: Cn1cc(C(=O)Cc2ccccc2)cn1
Reaction time: 3 h
Yield: 73.4 %

Procedure:
To a solution of N-methoxy-N,1-dimethyl-1H-pyrazole-4-carboxamide (4.6 g, 27.2 mmol) in anhydrous THF (50 mL) was added benzylmagnesium chloride (2.0 M in THF, 16.7 mL, 32.6 mmol) at −78° C. under N2, then stirred at the same temperature for 3 hours. The mixture was quenched with saturated NH4Cl solution, followed by a standard aqueous/EtOAc procedure. The crude was purified by silica gel column chromatography (PE:EtOAc=10:1) to give Intermediate 4 (4.0 g, yield 74%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[CH2:37](O)[CH2:38][CH2:39][CH:40]=C.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][CH2:26][CH2:40][CH2:39][CH:38]=[CH2:37])=[C:18]([CH3:24])[CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C=CCCCO
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: C=CCCCOC(=O)Nc1cc(C)c(Oc2ccnc3cc(OC)c(OC)cc23)cc1C
Yield: 105.5 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 4-penten-1-ol (20 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (71 mg, yield 100%).
Reaction SMILES: [CH:1](=[CH:8][C:9](=[O:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.F[B-](F)(F)F.O1CCCC1>CO>[C:2]1([CH:1]=[CH:8][CH:9]([OH:11])[CH3:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)C=Cc1ccccc1
Agent: F[B-](F)(F)F
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: C1CCOC1
Solvent: CO
Product: CC(O)C=Cc1ccccc1
Yield: 34.1 %

Procedure:
In a 200 ml stainless steel autoclave were charged 5 g (34.2 mmole) of benzalacetone and 0.213 g (0.171 mmole) of ##STR24## ((+)-BINAP)}BF4 synthesized in Example 4, and 3 ml of tetrahydrofuran and 2 ml of methanol were added thereto, followed by allowing the mixture to react at 30° C. under a hydrogen pressure of 50 kg/cm2 for 45 hours. The solvent was removed by distillation under reduced pressure (10 mmHg), and the reaction product was analyzed by GLC (PEG HT, 25 m, produced by Gasukuro Kogyo K. K.) to find the conversion to be 34.5%. The product was separated into the unreacted ketone and the hydrogenation product by silica gel column chromatography (eluent: hexane/ethyl acetate=4/1 by volume) to obtain 1.73 g of 4-phenyl-3-buten-2-ol having a purity of 89%. {α}25 D : +18.1°(c=5, CS2).
Reaction SMILES: Cl.[C:2]1([C:8]2([C:14]([OH:16])=[O:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17]O.O=S(Cl)[Cl:21]>C(OCC)C>[ClH:21].[CH3:17][O:15][C:14]([C:8]1([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1)=[O:16]
Reactant: O=S(Cl)Cl
Reactant: CO
Reactant: O=C(O)C1(c2ccccc2)CCNCC1
Agent: Cl
Solvent: CCOCC
Product: COC(=O)C1(c2ccccc2)CCNCC1

Procedure:
4-phenyl-piperidine-4-carboxylic acid hydrochloride (from example 20.6) (2.67 g, 11 mmol) and methanol (35 mL) were combined. SOCl2 (0.9 mL, 12.34 mmol, 1.1 eq.) was added dropwise. The reaction was heated at reflux for 18 h. The reaction was concentrated in vacuo to obtain a residue. The residue was slurried in diethyl ether, filtered, and the solids were rinsed with diethyl ether to give the title compound.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:11]([O:13][C:14]1[C:19]([C:20]2[NH:21][C:22](=[O:38])[C:23]3[C:24](=[C:26]([CH2:36][CH3:37])[N:27]([CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)[N:28]=3)[N:25]=2)=[CH:18][C:17]([S:39]([N:42]2[CH2:47][CH2:46][N:45]([CH2:48][CH3:49])[CH2:44][CH2:43]2)(=[O:41])=[O:40])=[CH:16][N:15]=1)[CH3:12].[CH2:50]([O:52]CCO)[CH3:51]>>[CH2:50]([O:52][CH2:12][CH2:11][O:13][C:14]1[C:19]([C:20]2[NH:21][C:22](=[O:38])[C:23]3[C:24](=[C:26]([CH2:36][CH3:37])[N:27]([CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)[N:28]=3)[N:25]=2)=[CH:18][C:17]([S:39]([N:42]2[CH2:47][CH2:46][N:45]([CH2:48][CH3:49])[CH2:44][CH2:43]2)(=[O:40])=[O:41])=[CH:16][N:15]=1)[CH3:51]
Reactant: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1-c1nc2c(CC)n(Cc3ccccn3)nc2c(=O)[nH]1
Reactant: CCOCCO
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Product: CCOCCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1-c1nc2c(CC)n(Cc3ccccn3)nc2c(=O)[nH]1
Temperature: 90 °C
Reaction time: 18 h
Yield: 68 %

Procedure:
A stirred mixture of potassium bis(trimethylsilyl)amide (434 mg, 2.2 mmol) and 2-ethoxyethanol (2 ml) was heated at 90° C. for 30 minutes, then allowed to cool. A solution of the title compound of Example 1 (153 mg, 0.27 mmol) in 2-ethoxyethanol (2 ml) was added and the reaction mixture stirred at 110° C. for 18 hours, then allowed to cool. The resulting mixture was evaporated under reduced pressure and the residual, brown oil purified by column chromatography on silica gel, using dichloromethane:methanol (95:5) as eluant, to furnish the title compound (110 mg, 68%) as a yellow foam. δ (CDCl3): 1.04 (3H, t), 1.31 (6H, m), 2.41 (2H, q), 2.54 (4H, m), 3.04 (2H, q), 3.14 (4H, m), 3.72 (2H, q), 3.90 (2H, t), 4.78 (2H, t), 5.67 (2H, s), 7.10 (1H, d), 7.22 (1H, m), 7.63 (1H, m), 8.57 (1H, d), 8.62 (1H, s), 8.99 (1H, s), 10.78 (1H, s). LRMS: m/z 597 (M+1)+.
Reaction SMILES: C([N:8]1[CH2:30][CH2:29][C:12]2=[C:13]([CH2:20][CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[N:11]2[CH2:10][CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+].CO>[Pd].ClCCl>[O:22]([CH2:21][CH2:20][C:13]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=2[N:11]2[CH2:10][CH2:9][NH:8][CH2:30][CH2:29][C:12]=12)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: c1ccc(CN2CCc3c(CCOc4ccccc4)c4ccccc4n3CC2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CO
Product: c1ccc(OCCc2c3n(c4ccccc24)CCNCC3)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 97.5 %

Procedure:
(Chart D, Step 4): A dry round bottom flask is charged with 3-benzyl-11-(2-phenoxyethyl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indole (317 mg, 0.80 mmol), ammonium formate (254 mg, 4.0 mmol), methanol (18 mL) and dichloromethane (3.2 mL). After the addition of 10% Pd/C (64 mg) the reaction is stirred at ambient temperature for two days. The reaction mixture is filtered through a pad of celite, and the catalyst is rinsed with methanol. The filtrates are combined and concentrated to 380 mg of a crude solid. This material is recrystallized from ethyl acetate/methanol/ethyl ether to afford 239 mg of 11-(2-phenoxyethyl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indole as a white solid. IR (drift) 3026, 3015, 2998, 2983, 2948, 2910, 2869, 2806, 2781, 2752, 1468, 1451, 1245, 755, 746 cm−1.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[CH3:12][C@H:13]1[NH:18][C@@H:17]([CH3:19])[CH2:16][NH:15][CH2:14]1.[CH2:20]=O>C(O)C>[CH3:19][C@H:17]1[NH:18][C@@H:13]([CH3:12])[CH2:14][N:15]([CH2:20][C:3]2[C:4]3[O:8][CH2:7][C:6](=[O:9])[C:5]=3[CH:10]=[CH:11][C:2]=2[OH:1])[CH2:16]1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: C=O
Reactant: O=C1COc2cc(O)ccc21
Solvent: CCO
Product: C[C@@H]1CN(Cc2c(O)ccc3c2OCC3=O)C[C@H](C)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.3 %

Procedure:
A solution of 6-hydroxybenzofuran-3(2H)-one (0.300 g, 2.00 mmol) in ethanol (2 mL) was added with cis-3,5-dimethylpiperazine (0.288 g, 2.00 mmol), and 37% aqueous formaldehyde (0.162 g, 2.00 mmol) at room temperature. The reaction mixture was stirred overnight at room temperature, and then concentrated. The resulting solid was dissolved in ethyl acetate, and the precipitated solid was removed by filtration. The filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain 7-[(cis-3,5-dimethylpiperazin-1-yl)methyl]-6-hydroxybenzofuran-3(2H)-one (0.173 g, 31%).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)[C:3]=1[C:16]#[N:17].C(=O)([O-])[O-].[K+].[K+].[CH3:24][O:25][C:26](=[O:33])[CH2:27][CH2:28][CH2:29][N:30]=[C:31]=[O:32]>O1CCCC1>[C:16]([C:3]1[C:4]([C:7]2[CH:8]=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=2)=[N:5][S:6][C:2]=1[NH:1][C:31]([NH:30][CH2:29][CH2:28][CH2:27][C:26]([O:25][CH3:24])=[O:33])=[O:32])#[N:17]
Reactant: N#Cc1c(-c2ccc([N+](=O)[O-])cc2)nsc1N
Reactant: COC(=O)CCCN=C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)CCCNC(=O)Nc1snc(-c2ccc([N+](=O)[O-])cc2)c1C#N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.1 %

Procedure:
A solution of 5-amino-3-(4-nitrophenyl)isothiazole-4-carbonitrile (25.0 g, 0.101 mol) in tetrahydrofuran (300 mL) dimethylsulfoxide (40 mL) at ambient temperature was treated with potassium carbonate (35.0 g, 0.25 mol). The resulting mixture was stirred at ambient temperature for 15 min. The reaction mixture was treated with 4-isocyanato-butyric acid methyl ester (21.8 g, 0.15 mol) at ambient temperature. The mixture was stirred at ambient temperature overnight. The reaction mixture was filtered through celite and filtrate concentrated in vacuo. The residue was dissolved EtOAc (600 mL) and washed with water and brine then dried (sodium sulfate), filtered, solvent concentrated in vacuo. The crude residue was purified by column chromatography (20% ethyl acetate in dichloromethane) to give the title compound as a light brown solid (31.5 g, 78%).
Reaction SMILES: [C:1]([CH:4]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][O:25][Si:26]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28])=[CH:20][CH:19]=1)[CH2:5][NH:6][C:7]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11](O)=[O:12])=[O:8])([OH:3])=O.C(Cl)CCl.[NH2:40][C:41]1[CH:42]=[C:43]2[C:48](=[CH:49][CH:50]=1)[CH:47]=[N:46][CH:45]=[CH:44]2>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[O:12]=[C:11]1[C:10]2[C:9](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7](=[O:8])[N:6]1[CH2:5][CH:4]([C:18]1[CH:19]=[CH:20][C:21]([CH2:24][O:25][Si:26]([CH:33]([CH3:35])[CH3:34])([CH:27]([CH3:28])[CH3:29])[CH:30]([CH3:32])[CH3:31])=[CH:22][CH:23]=1)[C:1]([NH:40][C:41]1[CH:42]=[C:43]2[C:48](=[CH:49][CH:50]=1)[CH:47]=[N:46][CH:45]=[CH:44]2)=[O:3]
Reactant: Nc1ccc2cnccc2c1
Reactant: CC(C)[Si](OCc1ccc(C(CNC(=O)c2ccccc2C(=O)O)C(=O)O)cc1)(C(C)C)C(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CC(C)[Si](OCc1ccc(C(CN2C(=O)c3ccccc3C2=O)C(=O)Nc2ccc3cnccc3c2)cc1)(C(C)C)C(C)C
Reaction time: 8 h

Procedure:
To 2-(2-carboxy-2-(4-((triisopropylsilyloxy)methyl)phenyl)ethylcarbamoyl)benzoic acid (E135) in pyridine was added EDC, DMAP and 6-aminoisoquinoline and the solution was flushed with N2, capped, and stirred overnight. The mixture was poured into EtOAc/NaHCO3(sat) and the aqueous layer was further extracted with EtOAc. The organics were dried (MgSO4), filtered, and evaporated. Column chromatography (SiO2, 5% MeOH/CH2Cl2) gave pure 3-(1,3-dioxoisoindolin-2-yl)-N-(isoquinolin-6-yl)-2-(4-((triisopropylsilyloxy)methyl)phenyl)propanamide (E136).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][C:12]([CH3:15])([CH3:14])[CH2:11][C:10]([CH3:17])([CH3:16])[C:9]=2/[CH:18]=[CH:19]/[CH:20]=[O:21])=[CH:4][CH:3]=1.[C:22](O)(=[O:24])[CH3:23].[C:26]([O:29][CH2:30]C)(=[O:28])[CH3:27]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:13][C:12]([CH3:14])([CH3:15])[CH2:11][C:10]([CH3:16])([CH3:17])[C:9]=2/[CH:18]=[CH:19]/[CH:20]([OH:21])[CH2:23][C:22](=[O:24])[CH2:27][C:26]([O:29][CH3:30])=[O:28])=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: CC1(C)CC(c2ccc(F)cc2)=C(/C=C/C=O)C(C)(C)C1
Reactant: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)CC(=O)CC(O)/C=C/C1=C(c2ccc(F)cc2)CC(C)(C)CC1(C)C
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To the yellow solution of the dianion was added a 0.25 M THF solution of 8.58 g (30 mmoles) of the aldehyde prepared in Step 7. The addition took 30 minutes. The reaction mixture was stirred an additional 30 minutes at -10° C., then quenched with 9.47 (165.6 mmoles) of acetic acid in 40 ml of THF. The reaction mixture was poured into ethyl acetate and extracted with H2O, saturated NaHCO3 and brine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][N:5]1[CH2:11][C:10]([CH2:12][NH2:13])=[CH:9][CH2:8][CH:7]([NH:14][C:15]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][N:18]=2)=[O:16])[C:6]1=[O:27].[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(N(CC)CC)C.CO>C1COCC1>[CH3:1][O:2][C:3](=[O:28])[CH2:4][N:5]1[CH2:11][C:10]([CH2:12][NH:13][C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:9][CH2:8][CH:7]([NH:14][C:15]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][N:18]=2)=[O:16])[C:6]1=[O:27]
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)CN1CC(CN)=CCC(NC(=O)c2nccc3ccccc23)C1=O
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)CN1CC(CNC(=O)c2ccccc2)=CCC(NC(=O)c2nccc3ccccc23)C1=O
Yield: 46 %

Procedure:
To a solution of {6-(aminomethyl)-3-[(isoquinoline-1-carbonyl)-amino]-2-oxo-2,3,4,7-tetrahydro-azepin-1-yl}-acetic acid methyl ester, 29, (0.14 g, 0.37 mmol) in THF(1 mL) is added benzoyl chloride (80 μl, 0.75 mmol) and triethyl amine (0.71 mL, 4.99 mmol). The reaction is complete with a few minutes. Methanol (5 mL) is added to the reaction mixture and then the solvents are removed in vacuo to provide a residue which is purified by HPLC to afford 84 mg (46% yield) of the desired product. 1H NMR (CDCl3) δ 9.37–9.33 (d, J=9.4 Hz, 1H), 9.06–9.03 (d, J=5.5 Hz, 1H), 7.73–7.64 (m, 4H), 7.59–7.48 (m, 2H), 7.41–7.48 (m, 4H), 5.68 (bs, 1H), 5.37–5.30 (m, 1H), 4.644.57 (d, d, J=17.5, 2.37 Hz, 1H), 4.4.6–4.40 (d, J=17.6 Hz, 1H), 4.15–4.08 (d, d, J=14.5, 6.9 Hz, 1H), 3.82–3.76 (d, J=17.6 Hz, 1H), 3.76–3.70 (d, d, J=14.7 Hz, 1H), 3.42 (s, 3H), 3.38–3.33 (d, J=17.6 Hz, 1H), 2.81–2.76 (m, 1H), 2.35–2.25 (d, d, J=16.3, 14.2 Hz, 1H); 13C (CDCl3) 172.6, 170.5, 168.0, 165.9, 148.2, 141.0, 137.7, 134.3, 133.8, 132.4, 132.3, 132.0, 130.7, 129.0, 128.9, 127.7, 127.6, 127.5, 127.2, 124.7, 52.6, 50.5, 49.3, 49.1, 46.7, 32.6; MS 487 (M+H).